Artemisinin (Qinghaosu)(I), a sesquiterpene lactone endoperoxide, is the first natural trioxane isolated from Artermisia annua, L.

The artemisinin is of special biological interest because of its outstanding antimalarial activity and outstanding activity against pneumocystis carinii and toxoplasma gondii. The anti-human immunodeficiency virus (HIV) activity of artemisinin derivatives has been also reported. Artemisinin has been subjected to a number of reviews because of its novel structure and outstanding antimalarial activity. Most first generation C-12 acetal type derivatives are hydrolytically unstable. Also, most semi-syntheses have involved replacing the C-12 acetal functionality in ether derivatives by less hydrolytically prone functional groups. Recently, however, C-12 non-acetal-type deoxoartemisinin (III) prepared from either artemisinin of formula (I) or artemisinic acid of formula (II) has been reported to show more antimalarial activity than that of artemisinin both in vitro and in vivo (see Jung, M.; Li, X.; Bustos, D. A.; ElSohly, H. N.; McChesney, J. D., A Short and Stereospecific Synthesis of (+)-Deoxoartemisinin and (−)-Deoxodesoxyartemisinin, Tetrahedron Lett., 1989, 30, 5973–5976 and Jung, M.; Li, X.; Bustos, D. A.; ElSohly, H. N.; McChesney, J. D.; Milhous, W. K., Synthesis and Antimalarial Activity of (+)-Deoxoartemisinin, J. Med. Chem., 1990, 33, 1516–1518).

Non-acetal-type analogs of deoxoartemisinin recently received attention owing to their better bioavailability, such as acid stability, than acetal-type analogs. Furthermore, evidence that analogs not possessing exo-oxygen at C-12 are less neurotoxic in animal studies than acetal type artemisinin is also emerging and may thus lead to the future abandonment of the currently clinically used acetal-type analogs (e.g., arteether, artemether, artesunate and artelinic acid). After the preparation of 12-n-butyldeoxoartemisinin as the first hydrolytically stable non-acetal type analog containing a C—C bond at C-12 was reported, a series of non-acetal-type derivatives including a few of heteroaryl and unsaturated substituents a C-12 have been prepared (See Jung, M.; Bustos, D. A.; ElSohly, H. N.; McChesney, J. D., A Concise and Stereoselective Synthesis of (+)-12-n-Butyldeoxoartemisinin, Synlett, 1990, 743–744 and Chorki, F.; Crousse, B.; Bonnet-Delpon, D.; Begue, J. P.; Brigaud, T.; Portella, C., C-10 Fluorinated Derivatives of Dihydroartemisinin: Difluoromethylene Ketones, Tetrahedron Lett., 2001, 42, 1487–1489).
Although most studies have focused on antimalarial activities, a few research groups have recently reported on cancer cell toxicity of artemisinin and it related derivatives. (see Woerdenbag, H. J.; Moskal, T. A.; Pras, N.; Maringle, T. M.; ElFeraly, F. S.; Kampinga, H. H.; Konings, A. W. T., Cytotoxicity of Artemisinin-related Endoperoxides to Ehrlich ascites Tumor cells, J. Nat. Prod., 1993, 56, 849 and Wu, J-M.; Shan F.; Wu, G-S.; Li, Y.; Ding, J.; Xiao, D.; Han, J-X.; Atassi, G; Leonce, S.; Caignard, D-H.; Renard, P., Synthesis and Cytotoxicity of Artemisinin derivatives containing Cyanoarylmethyl group, Eur. J. Med. Chem., 2001, 36(5), 469–479). Because of their higher rate of cell division, most cancer cells express a higher surface concentration of transferrin receptors than normal cells and have high rates of iron intake. A unique structure bearing endoperoxide could be a trigger for the generation of active oxygen radicals via hemolytic cleavage of the weak oxygen-peroxide bond accelerated by higher ferrous ion concentration of cancer cell, which may mediate for the selective and preferable damage to vital cellular structures of the relatively active cancer cells. Although some dimers of acetal type derivatives of artemisinin have been prepared and show anticancer activities, yields are low and most of them possess either aromatic linkers or still acetal types at the C-12 position, which are neurotoxic, acid unstable, and show low anticancer activities (see Galal, A. M.; Ahmad, M. S.; El-Feraly, F. S., Preparation and Characterization of a New Artemisinin-Derived Dimer, J. Nat. Prod., 1996, 59, 917–920; Posner, G. H.; Ploypradith, P.; Parker, M. H.; O'Dowd, H.; Woo, S-H.; Northrop, J.; Krasavin, M.; Dolan, P.; Kensler, T. W.; Xie, S.; Shapiro, Antimalarial, Antiproliferative, and Antitumor Activities of Artemisinin-Derived, Chemically Robust, Trioxane Dimers., J. Med. Chem., 1999, 42, 4275–4280; and Ekthawatchai, S.; Kamchonwongpaisan, S.; Kongsaeree, P.; Tarnchompoo, B.; Thebtaranonth, Y; Yuthavong, Y, C-16 Artemisinin Derivatives and Their Antimalarial and Cytotoxic Activities: Synthesis of Artemisinin Monomers, Dimers, Trimers, and Tetramers by Nucleophilic Additions to Artemisitene, J. Med. Chem., 2001, 44, 4688–4695).